Loteprednol (as the

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides a ...

loteprednol etabonate) is a topical corticosteroid used to treat inflammations of the eye. It is marketed by Bausch and Lomb as Lotemax and Loterex. It was patented in 1980 and approved for medical use in 1998.

Medical uses

Applications for this drug include the reduction of

inflammation Inflammation (from la, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molec ...

after eye surgery, seasonal

allergic conjunctivitis Allergic conjunctivitis (AC) is inflammation of the conjunctiva (the membrane covering the white part of the eye) due to allergy. Although allergens differ among patients, the most common cause is hay fever. Symptoms consist of redness (mainly due ...

uveitis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and in ...

, as well as chronic forms of

keratitis Keratitis is a condition in which the eye's cornea, the clear dome on the front surface of the eye, becomes inflamed. The condition is often marked by moderate to intense pain and usually involves any of the following symptoms: pain, impaired e ...

(e.g. adenoviral and Thygeson's keratitis), vernal keratoconjunctivitis, pingueculitis, giant papillary conjunctivitis, and

episcleritis Episcleritis is a benign, self-limiting inflammatory disease affecting part of the eye called the episclera. The episclera is a thin layer of tissue that lies between the conjunctiva and the connective tissue layer that forms the white of the e ...

Contraindications

As corticosteroids are

immunosuppressive Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...

, loteprednol is contraindicated in patients with viral,

fungal A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from th ...

or mycobacterial infections of the eye.

Adverse effects

The most common adverse effects in patients being treated with the gel formulation are anterior chamber inflammation (in 5% of people), eye pain (2%), and foreign body sensation (2%).

Interactions

Because long term use (more than 10 days) can cause increased intraocular pressure, loteprednol may interfere with the treatment of glaucoma. Following ocular administration, the drug is very slowly absorbed into the blood, therefore the blood level is limited to an extremely small concentration, and interactions with drugs taken by mouth or through any route other than topical ophthalmic are very unlikely.

Pharmacology

Mechanism of action

Corticosteroids mediate their anti-inflammatory effects mainly through the modulation of the cytosolic glucocorticoid receptor (GR) at the genomic level. Preclinical studies demonstrated that loteprednol etabonate is highly lipophilic and has strong binding affinity to glucocorticoid receptors. After it binds to the GR in the cytoplasm, the activated corticosteroid-GR complex migrates to the nucleus, where it upregulates the expression of anti-inflammatory proteins and represses the expression of proinflammatory proteins. Corticosteroids inhibit inflammatory cytokines, chemokines, adhesion molecules, and other inflammatory mediators. They also reduce synthesis of histamine, stabilize cell membranes, and inhibit degranulation of mast cells. Recent work suggests that the activated corticosteroid-GR complex also elicits nongenomic effects, particularly the inhibition of vasodilation, vascular permeability, and migration of leukocytes.

Pharmacokinetics

Neither loteprednol etabonate nor its inactive metabolites Δ¹- cortienic acid and Δ¹-cortienic acid

etabonate Etabonate or ethyl carbonate is the chemical group with formula –, or –. The names are also used for esters R–, for the anion [], and for salt (chemistry), salts of the latter. Pharmaceutical aspects "Etabonate" is an international no ...

are detectable in the bloodstream, even after oral administration. A study with patients receiving loteprednol eye drops over 42 days showed no

adrenal suppression Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal gland normally secretes glucocorticoids (primarily cortisol), mineralocorticoids (primarily aldosterone), and androge ...

, which would be a sign of the drug reaching the bloodstream to a clinically relevant extent.

Steroid receptor Steroid hormone receptors are found in the nucleus, cytosol, and also on the plasma membrane of target cells. They are generally intracellular receptors (typically cytoplasmic or nuclear) and initiate signal transduction for steroid hormones which ...

affinity was 4.3 times that of

dexamethasone Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...

in animal studies.

Retrometabolic drug design

Loteprednol etabonate was developed using retrometabolic drug design. It is a so-called soft drug, meaning its structure was designed so that it is predictably metabolised to inactive substances. These metabolites, Δ¹-cortienic acid and its etabonate, are derivatives of cortienic acid, itself an inactive metabolite of

hydrocortisone Hydrocortisone is the name for the hormone cortisol when supplied as a medication. Uses include conditions such as adrenocortical insufficiency, adrenogenital syndrome, high blood calcium, thyroiditis, rheumatoid arthritis, dermatitis, asthm ...

. File:Cortisol2.svg, Cortisol, a naturally occurring corticosteroid, known as

when used as a drug File:Delta1-cortienic acid skeletal.svg, Δ¹-Cortienic acid, inactive metabolite of loteprednol File:Cortienic acid skeletal.svg, Cortienic acid, inactive metabolite of hydrocortisone

Chemistry

Loteprednol etabonate is an ester of loteprednol with

(ethyl carbonate). The pure chemical compound has a melting point between and . Its solubility in water is 1:2,000,000, therefore it is formulated for ophthalmic use as either an ointment, a gel, or a suspension. Loteprednol is a corticosteroid. The ketone side chain of classical corticosteroids such as

is replaced by a cleavable ester, which accounts for the rapid inactivation. (This is not the same as the etabonate ester.)

Chemical synthesis